The objective of the proposed project is to develop a neuroprosthetic device that uses targeted, activity-dependent spinal stimulation to improve arm and hand motor recovery after cervical spinal cord injury (SCI). The project seeks to advance clinical practice through the use of brain-computer-interface technology to harness physiological mechanisms of neural plasticity. Motor deficits severely impact the quality of life of people with SCI, yet current treatments produce limited improvements in movement abilities. Recent clinical and experimental evidence suggests that electrical stimulation of the nervous system can be an effective therapy for a variety of neurological disorders. This preclinical project will evaluate novel application of electrical stimulation for rehabilitation of forelimb motor deficits in a rat model of SCI. The strategy is designed to enhance the function of spared neural pathways by directing Hebbian plasticity through targeted stimulation of volitionally activated neural circuits Results will lay the foundation for a future clinical trial using spinal stimulation in human subjets with SCI. Preliminary data demonstrate the effectiveness of one-channel, intraspinal stimulation triggered by activity of a forelimb muscle to improve motor performance in rats with chronic SCI. Specific Aim 1 seeks to optimize the one-channel intervention by exploring the use of electrocorticography signals to trigger stimulation rather than muscle activity, and of less invasive surface stimulation of the spinal cord. A new electrode technology will be deployed for cortical recording and surface stimulation. Specific Aim 2 will develop multi-channel stimulation to extend the capacity of the therapy. Specific Aim 3 will determine if the therapy can produce further recovery if introduced during the subacute phase of SCI. Specific Aim 4 begins an investigation of the mechanisms of action of the intervention to suggest refinements and combinatorial therapies to facilitate further recovery. Physiological and immunohistochemical approaches will be employed to identify reorganized descending and reflex pathways, effects on serotonin regulation of spinal excitability, and changes in the structure of spinal perineuronal nets that could promote synaptic plasticity.